Biology subjects

De Angelis, F.

Publications and source records attributed to De Angelis, F..

17 recordsLinked to original sources

bioRxiv2026

Hierarchical dendrite-inspired organic bioelectronic interfaces for neuronal integration

Brain-machine interfaces rely on intimate electrical communication between living neurons and artificial materials, yet conventional electrode architectures remain structurally different to neuronal tissue, limiting stable cell-electrode coupling and long-term recording. Although conducting polymers and microstructured interfaces have individually improved the electrochemical and biological properties of neural electrodes, integrating neuromimetic architecture with electrically active organic materials to direct neuron-electrode interactions has remained challenging. Here we engineer dendrite-inspired organic microelectrodes by programming the self-assembly of conducting polymer fibers directly on microelectrode arrays. By controlling the electrodeposition process, we generate hierarchical architectures that emulate key stages of dendritic development while preserving the relevant electrochemical properties of conducting polymers. These bioinspired interfaces promote nanoscale membrane conformability, reduce the neuron-electrode cleft, and induce localized membrane engulfment of the electrode structures. The enhanced structural integration is accompanied by increased synaptic protein expression and neuronal excitability within mature primary cortical networks. Furthermore, the dendritic electrodes enable localized laser-assisted optoporation, providing transient intracellular electrophysiological access while maintaining extracellular recording functionality.

neuroscience↗

bioRxiv2026

On the Edge of Empire: Paleogenomic Insights into Roman Dacia

The Roman province of Dacia, located north of the Danube frontier, represented a key zone of cultural and demographic interaction during the Imperial period. However, the biological impact of Roman colonization in this region has not been characterized using genomic data. Here, we analyze genome-wide data from 34 individuals recovered from the Apulum-Dealul Furcilor necropolis, one of the largest funerary complexes in Roman Dacia. The genome-wide data reveal pronounced genetic heterogeneity within this population, reflecting its position at the intersection of Eastern Europe, the Mediterranean, and West Asia. Notably, we observe a sex-biased pattern of ancestry. Female individuals show stronger affinities to Eastern European, Steppe, and Caucasus-associated populations, suggesting the persistence of local or regionally connected genetic lineages. In contrast, male individuals display closer genetic relationships with Mediterranean and North African groups, including populations associated with Roman and Punic contexts, indicating male-mediated gene flow linked to long-distance mobility. These findings highlight the complex demographic processes shaping Roman frontier communities, where local and incoming populations were integrated through asymmetric social dynamics. Our results provide genomic evidence consistent with sex-biased admixture in Roman Dacia and underscore the role of frontier regions as hubs of genetic and cultural interaction within the Roman Empire.

genomics↗

bioRxiv2026

The Genomic Legacy of the Norman Conquest in Rural England

The Norman Conquest of 1066 CE reshaped the political and cultural landscape of England, yet its demographic consequences remain poorly understood, particularly outside elite and urban contexts where historical evidence is concentrated. Here, we investigate the population history of a rural English community spanning the Conquest using genome-wide ancient DNA from the Priory Orchard site, a cemetery in Godalming (Surrey) in use between the 9th and early 13th centuries CE. We generated genomic data from 78 individuals and established radiocarbon dates for 98 individuals from the site. Population genetic analyses place Priory Orchard individuals within the genetic continuum of early medieval populations from the North Sea region. Ancestry modelling indicates that this rural community carried substantial Scandinavian/Viking-related ancestry alongside a persistent Saxon-related component and a smaller French-related contribution. However, stratifying individuals by date, before and after 1066 CE, reveals no clear genome-wide discontinuity across the Conquest horizon, suggesting demographic continuity through this crucial political and social transition. This pattern is consistent with historical and archaeological evidence indicating that many of the most visible transformations following the Conquest occurred primarily among the elite. Our results provide the first genomic perspective on communities living through the Norman Conquest and indicate that rural southern England saw persistent migration links with other areas facing the North Sea rather than abrupt population replacement.

genetics↗

bioRxiv2026

Temporal shifts in polygenic traits track major epidemics in Western Eurasia

Infectious diseases are recognized as one of the strongest selective forces, exerting a profound influence on the genetic makeup of human populations over time. Recently, large-scale genome-wide association studies (GWAS) on immunological traits have underscored the notion that genetic predisposition to infectious diseases likely stems from the contribution of several thousand loci across the human genome. To model the polygenic inheritance of these traits, multiple variants can be combined into polygenic risk scores (PRS), which estimate an individuals genetic predisposition for a trait. By combining present-day GWAS statistics from large European biobanks with genomic data from more than 3,500 ancient individuals from Western Eurasia, we characterize temporal changes in four highly heritable infectious disease-related traits over a span of 10,000 years. In doing so, we account for variation in these traits across time, space, and genetic ancestries, and demonstrate that the observed patterns cannot be explained by genetic drift alone. Our findings suggest that major disease outbreaks in human history are associated with shifts in polygenic traits in human populations. Specifically, three events - the Justinian Plague, Antonine Plague, and early medieval measles outbreaks - coincide with significant shifts in the polygenic profiles of these traits. Using a Gene Ontology enrichment approach, we show that these shifts involve multiple systemic biological processes, with a consistent emphasis on metabolic pathways modulating immunological responses both directly and indirectly.

genomics↗

bioRxiv2026

A Translational Preclinical Strategy for Chronic Spinal Cord Injury: Neuroprotective and Regenerative Potential of Botulinum Neurotoxin Type A combined with Muscle Atrophy Prevention via Electrostimulation

BackgroundSpinal cord injury (SCI) triggers persistent neuroinflammation, gliosis, neuronal loss, and demyelination, leading to motor deficits and neuropathic pain. Botulinum neurotoxin type A (BoNT/A) has shown anti-inflammatory and neuroprotective effects in acute SCI, but its potential in the chronic phase remains unclear. This study investigates whether combining BoNT/A with electrical muscle stimulation (EMS) enhances recovery in chronic SCI. MethodsAdult mice with severe thoracic SCI (paraplegic) underwent EMS (30 min/day for 10 non-consecutive days starting 3 days post-injury) or no stimulation. Fifteen days after SCI, animals received a single intrathecal injection of BoNT/A (15 pg/5 L) or saline. Functional recovery was assessed up to 60 days as well as in moderate and mild SCI mice, neuropathic pain onset and maintenance were evaluated. Spinal cord tissue was analysed for astrocytic and microglial morphology, neuronal and oligodendroglia survival, myelin protein expression, and in vitro effects on oligodendrocyte precursor cells (OPCs). The phenotype of hindlimb muscles was evaluated through morphological and gene expression analyses. ResultsEMS was able to counteract muscle atrophy and fibrosis, and when combined with BoNT/A, also denervation. Moreover, the combination restored hindlimb motor function in chronic SCI, whereas BoNT/A or EMS alone were ineffective. Neuropathic pain, a common comorbidity associated with SCI, was mitigated by BoNT/A treatment even when administered in the chronic phase. BoNT/A reduced astrocytic hypertrophy and excitatory synapse association and was associated with a morphology-based redistribution of microglial profiles toward a resting-like classification, decreased apoptosis, and increased neuronal and oligodendroglia survival. Myelin basic protein expression was significantly elevated in vivo. In vitro, BoNT/A promoted OPC differentiation into myelinating oligodendrocytes, increased process complexity, and upregulated Myelin basic protein, galactocerebroside C, proteolipid protein, and myelin oligodendrocyte glycoprotein under both proliferative and differentiating conditions. Cleaved SNAP25 colocalization with OPC confirmed direct BoNT/A internalization and activity. ConclusionsBoNT/A exerts multi-cellular neuroprotective actions in chronic SCI, supporting neuronal and oligodendroglia survival, reducing neuroinflammation, enhancing remyelination and the combination with EMS promotes substantial recovery of muscle homeostasis within a permissive microenvironment shaped by early stimulation. Its efficacy depends on a permissive microenvironment achieved through EMS. These results provide strong rationale for the clinical evaluation of BoNT/A as a therapeutic strategy for chronic SCI.

neuroscience↗

bioRxiv2025

Characterisation of the Tilapia Lake Virus proteome and identification of an 11th protein, S9-F3

Tilapia Lake Virus (TiLV) is an emerging negative-sense, single-stranded RNA virus that poses a significant threat to global tilapia aquaculture. Of the proteins encoded by its ten genomic segments, the first four, which encode a viral polymerase (segments 1-3) and a nucleoprotein (segment 4) have been characterised. However, the functions of the polypeptides encoded by the remaining segments remain largely unknown. Here, we systematically investigated the expression and subcellular localisation of all ten predicted TiLV-encoded proteins using in vitro translation and expression in mammalian and fish cells as well as mass spectrometry of virus infected cells. These approaches confirmed the synthesis of major polypeptides from each segment and identified an additional 11th protein, S9-F3, translated from an alternative reading frame of segment 9. Microscopy of individually expressed green fluorescent protein (GFP)-tagged constructs revealed that S2 and S10 polypeptides were predominantly nuclear, while S1, S3, S5, S8 and S9-F3 were mostly cytoplasmic with S5 and S6 displaying perinuclear foci. Bioinformatic analysis suggested a potential nuclear export signal in S9-F3 and use of the inhibitor leptomycin B confirmed its CRM1-dependent nuclear export. Evolutionary analyses indicated that both S9 and S9-F3 are under selective pressure, as well as the presence of an S9-F3 homologue in a TiLV-like guppy virus. These findings uncover an alternative translation product and a regulated nuclear export mechanism in TiLV, providing new insights into the molecular biology of this virus and its interaction with host cellular pathways.

microbiology↗

bioRxiv2025

Metabolic resilience rules sex-specific pain recovery during hormonal aging: a multi-omics analysis of neuropathy in mice.

Biological aging and sex interact to shape systemic metabolism, yet their role in chronic pain resolution remains unexplored. We hypothesized that metabolic resilience -- the ability to flexibly switch fuel sources and maintain energy homeostasis -- rules successful recovery from nerve injury in a sex-dependent manner during aging. In 12-month-old male and female mice -- corresponding to the perimenopausal phase in females and the onset of hormonal decline in both sexes -- we induced sciatic nerve chronic constriction injury and performed multi-omics profiling during Wallerian degeneration, a phase known to trigger long-term neurobiological remodeling. Aging females exhibited early activation of fatty acid oxidation, increased resting energy expenditure, upregulation of mitochondrial redox enzymes and circulating progesterone and corticosterone. Proteomic and metabolomic analysis revealed pentose phosphate pathway enrichment and gluconeogenesis, supporting redox balance and metabolic flexibility. Conversely, males displayed persistent glycolytic reliance, long-chain acylcarnitine accumulation, suppression of adiponectin and PPAR{gamma}, indicating metabolic inflexibility. Longitudinal behavioral analysis revealed that aging females recovered earlier and more fully than aging males, reversing the pattern previously shown in our adult mouse study, where females developed persistent pain and males recovered rapidly. These patterns highlight a non-linear, sex-specific interaction between biological aging and injury response, where hormonal decline reprograms the metabolic trajectory and reshapes pain outcomes. Metabolic resilience governs sex-specific recovery following nerve injury by directing early systemic adaptations that precede and predict long-term pain trajectories. These results define mechanistically anchored, sex- and age-specific biomarkers, and propose preclinical targets for timely, personalized interventions in age-associated neuropathic pain.

neuroscience↗

bioRxiv2024

A photo-switchable gold nanoformulation based on the dCas9 protein for spatiotemporal controlled gene editing activation in vivo

Genome editing allows for the manipulation of genomic DNA for biotechnology and biomedical applications, but the specificity and control of the editing process remain a challenge. This study introduces a nano-switch for spatiotemporal control of the editing process. The basic module of the nano-switch (the monomer) is composed of a gold nanorod conjugated with the dead Cas9. Based on mathematical models, we established the design and the mechanism of action of the nano-switch. Briefly, when two monomers, guided by their respective guide RNAs, form a dimer onto the DNA and get irradiated with a Near-Infrared pulsed laser resonant at the plasmonic properties of the dimer, they generate a localized heat that triggers a thermal break onto the DNA. The nano-switch was generated, validated, and tested in zebrafish embryos at the 1-cell stage. Molecular analysis of irradiated embryos showed targeted DNA mutations, validating the efficacy of the nano-switch as a tool for conditional gene editing that integrates the if-when-where functions.

molecular biology↗

bioRxiv2024

High-frequency extracellular spiking in electrically-active cancer cells

Microelectrode matrices have been extensively used in the past 30 years as a reliable platform to record the extracellular activity of cells traditionally regarded to as excitable, i.e. brain cells and muscle cells. Meanwhile, fundamental biology studies on cancer cells since the 1970s reveal that they exhibit altered functionalities of ion channels, membrane potentials, metabolism, and communication mechanisms when compared to their healthy counterparts. In this work, we present for the first time the presence of extracellular voltage spikes occurring at high frequencies (0.1-3.5 kHz) in breast cancer cells, resembling the ones observed in excitable cells, and the possibility to record them with 30 {micro}m TiN microelectrode matrices. These preliminary findings may open a new path for exploration in a variety of research fields, enabling the access to bioelectrical dynamics in cancer cells and cell networks, targeting bioelectricity as a tool in anticancer drug development and cancer diagnostics, as well as provide a market expansion for companies commercializing microelectrodes and microelectrode recording systems.

bioengineering↗

bioRxiv2024

MEA-NAP compares microscale functional connectivity, topology, and network dynamics in organoid or monolayer neuronal cultures

Microelectrode array (MEA) recordings are commonly used to compare firing and burst rates in neuronal cultures. MEA recordings can also reveal microscale functional connectivity, topology, and network dynamics--patterns seen in brain networks across spatial scales. Network topology is frequently characterized in neuroimaging with graph theoretical metrics. However, few computational tools exist for analyzing microscale functional brain networks from MEA recordings. Here, we present a MATLAB MEA network analysis pipeline (MEA-NAP) for raw voltage time-series acquired from single- or multi-well MEAs. Applications to 3D human cerebral organoids or 2D human-derived or murine cultures reveal differences in network development, including topology, node cartography, and dimensionality. MEA-NAP incorporates multi-unit template-based spike detection, probabilistic thresholding for determining significant functional connections, and normalization techniques for comparing networks. MEA-NAP can identify network-level effects of pharmacologic perturbation and/or disease-causing mutations and, thus, can provide a translational platform for revealing mechanistic insights and screening new therapeutic approaches.

neuroscience↗

bioRxiv2022

Deep brain cancer metastasis detection with wide-volume Raman spectroscopy through a single tapered fiber

We propose a low-invasive method to enable implantable, large volume Raman spectroscopy in arbitrarily deep brain regions of the mouse brain. Using a single tapered fiber as thin as 1 m at the tip, we identified diagnostic markers of brain metastasis - the most frequent brain tumor in human adults - with overall accuracy [≥] 90%. We view our approach as a promising complement to the existing palette of tools for optical interrogation of the brain.

neuroscience↗

bioRxiv2022

Chronic cardiotoxicity assessment by cell optoporation on microelectrode arrays

The reliable identification of chronic cardiotoxic effects in in vitro screenings is fundamental for filtering out toxic molecular entities before in vivo animal experimentation and clinical trials. Present techniques such as patch-clamp, voltage indicators, and standard microelectrode arrays do not offer at the same time high sensitivity for measuring transmembrane ion currents and low-invasiveness for monitoring cells over long time. Here, we show that optoporation applied to microelectrode arrays enables measuring action potentials from human-derived cardiac syncytia for more than 1 continuous month and provides reliable data on chronic cardiotoxic effects caused by known compounds such as pentamidine. The technique has high potential for detecting chronic cardiotoxicity in the early phases of drug development.

pharmacology and toxicology↗

bioRxiv2022

Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program

The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic change over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). The MVP was divided into five birth cohorts (N-range=123,888 [born from 1943-1947] to 136,699 [born from 1948-1953]). Groups of participants were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP+HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010<Cohens d<0.259, p<7.80x10-4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept=1.08{+/-}0.042). The 1kGP+HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction=0.045{+/-}0.007, p<0.05) confounding in the GWAS statistics. This study provides a comprehensive characterization of ancestry diversity of the MVP cohort over time and highlights that more refined modeling of genetic diversity (e.g., the 1kGP+HGDP-based ancestry assignment) can more accurately capture the polygenic architecture of traits and diseases that could be affected by population stratification.

genomics↗

bioRxiv2021

Isotopic evidence for population dynamics in the Central Italian Copper Age and Bronze Age.

The mobility patterns in the Italian peninsula during prehistory are still relatively unknown. The excavation of the Copper Age and Bronze Age deposits in La Sassa cave (Sonnino, Italy) allowed to broaden the knowledge about some local and regional dynamics. We employed a multi-disciplinary approach, including stable (carbon and nitrogen - C and N, respectively) and radiogenic (strontium-Sr) isotopes analyses and the identification of the cultural traits in the material culture to identify mobility patterns that took place in the region. The Sr isotopic analyses on the human bones show that in the Copper Age and at the beginning of the Bronze Age, the cave was used as a burial place by different villages, perhaps spread in a radius of no more than 5 km. Stable isotopes analyses suggest the introduction of C4 plants in the diet of the Middle Bronze Age (MBA) communities in the area. Remarkably, in the same period, the material culture shows increasing influxes coming from the North. This evidence is consistent with the recent genomic findings tracing the arrival of people carrying a Steppe-related ancestry in Central Italy in MBA.

evolutionary biology↗

bioRxiv2021

The impact of evolutionary processes in shaping the genetics of complex traits in East Asia and Europe: a specific contribution from Denisovan and Neanderthal introgression

Evidence of how human evolution shaped the polygenicity of human traits and diseases has been extensively studied in populations of European descent. However, limited information is currently available about its impact on other ancestry groups. Here, we investigated how different evolutionary processes affected the common variant heritability of traits and diseases in East Asians. Leveraging genome-wide association statistics from the Biobank Japan (up to 158,284 participants), we assessed natural selection (negative and positive), archaic introgression from Neanderthal and Denisova, and several genomic functional categories with respect to the heritability of physiological and pathological conditions. Similar to reports in European descent populations, the heritability estimates for East Asian traits were ubiquitously enriched for negative selection annotations (false discovery rate, FDR q<0.05). Enrichment of Denisovan introgression was identified in coronary artery disease (1.69-fold enrichment, p=0.003). We followed up these enrichments by conducting a phenome-wide association study (PheWAS) of Denisovan and Neanderthal alleles in participants of six ancestral backgrounds from the UK Biobank. In East Asians, Denisovan-inherited alleles were associated with 22 phenotypes, including metabolic, immunological, cardiovascular, endocrine, and dermatological traits. The strongest association was observed for the Denisovan-inherited locus rs59185462 with rheumatoid arthritis (beta=0.82, p=1.91x10-105). In summary, our study provides the first evidence regarding the impact of evolutionary processes on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in East Asian populations.

genetics↗

bioRxiv2017

Progression of regional grey matter atrophy in multiple sclerosis

Grey matter atrophy is present from the earliest clinical stages of multiple sclerosis (MS), but the temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in MS, and its association with disability accumulation.\n\nIn this longitudinal study, we included 1,417 subjects: 253 with clinically-isolated syndrome (CIS), 708 relapsing-remitting MS (RRMS), 128 secondary-progressive MS (SPMS), 125 primary-progressive MS (PPMS), and 203 healthy controls from 7 European centres. Subjects underwent repeated MRI scanning (total number of scans 3,604); the mean follow-up for patients was 2.41yrs (SD{+/-}1.97). Disability was scored using the Expanded Disability Status Scale (EDSS). We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template. We used an established data-driven event-based model (EBM) to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific EBM stage, based on the number of their atrophic regions. We used nested linear mixed-effects regression models to explore the associations between the rate of increase in the EBM stages over time, disease duration and annual rate of EDSS gain.\n\nThe first regions to become atrophic in CIS and relapse-onset MS patients (RRMS and SPMS) were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. The sequence of atrophy in PPMS showed a similar involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset MS and late atrophy in PPMS. Patients with SPMS showed the highest EBM stages (highest number of atrophic regions, all p<0.001) at study entry. Rates of increase in EBM stages were significantly different from healthy controls in all MS phenotypes, except for CIS. The increase in the number of atrophic regions (EBM stage) was associated with disease duration in all patients. EBM stage was associated with disability accumulation in RRMS independent of disease duration (p<0.0001).\n\nThis data-driven staging of atrophy progression in a large MS sample demonstrates that grey matter atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across MS phenotypes. The spread of atrophy was associated with disease duration, and disability accumulation in RRMS.\n\nAbbreviations

neuroscience↗

bioRxiv2017

Deep grey matter volume loss drives disability worsening in multiple sclerosis

ObjectiveGrey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.\n\nMethodsWe analysed 3,604 brain high-resolution T1-weighted MRI scans from 1,417 participants: 1,214 MS patients (253 clinically-isolated syndrome[CIS], 708 relapsingremitting[RRMS], 128 secondary-progressive[SPMS], 125 primary-progressive[PPMS]), over an average follow-up of 2.41 years (standard deviation[SD]=1.97), and 203 healthy controls (HCs) [average follow-up=1.83 year, SD=1.77], attending 7 European centres. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression.\n\nResultsSPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio=0.73, 95% CIs 0.65, 0.82; p<0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%)[p<0.01]. The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%) (all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta=0.04, p<0.001).\n\nInterpretationThis large multi-centre and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.

neuroscience↗